This invention relates to oral rehydration products for the treatment of mammals suffering from gastrointestinal disorders which may arise from nutritional, parasitic, prional, bacterial, viral or protozoal causes and lead to fluid depletion, acidosis, and imbalances or loss of essential electrolytes. These diseases are causes clinical signs that are more severe in young animals and children, but may occur in adults of any species. Dehydration and electrolyte imbalances can cause death.
Normal Digestion
The functional goal of digestion is to break down complex foodstuffs into small component parts (nutrients) that can be absorbed by the intestine into the body, where said nutrients can be re-assembled into complex molecules that are necessary for the performance of normal body metabolism. The three major classes of foodstuffs are protein, carbohydrate and fat which are broken down into amino acids, sugars and lipids, respectively. Water and electrolytes (which are minerals such as sodium, potassium, chloride, and magnesium) are also required for maintenance of normal body metabolism. The ability of the gastrointestinal (GI) tract to digest food depends on a complex interaction of neuroendocrine responses that cause secretion of digestive enzymes and control the motility of the intestinal organs.
The first step in digestion is mechanical breakdown of the food, which is accomplished through chewing in the mouth, and then churning in the stomach. The stomach also serves as a reservoir in which digestive enzymes are mixed with the ingesta, causing the food to be broken down into a slurry. The slurry then passes from the stomach to the small intestine. The absorption of nutrients and electrolytes is almost entirely accomplished through the small intestine, whilst the large intestine is largely responsible for the resorption of water. The non-digestible residue of ingesta is excreted as feces.
In mammals with only one stomach, such as dogs, cats, pigs and humans, the digestive processes occur as described above. In herbivores (such as rabbits and horses) and ruminants (such as cattle and sheep), normal digestion also depends heavily on the activity of the microflora (bacteria, yeasts, and protozoa) of the rumen in ruminants, or of the cecum in horses and rabbits. The microflora in these species can digest cellulose; ferment carbohydrates to volatile fatty acids; and convert nitrogenous substances to ammonia, amino acids, and protein. In certain circumstances, the activity of the microflora can be suppressed to the point that digestion becomes abnormal or ceases. Incorrect diet, prolonged starvation or inappetence, and hyperacidity (as occurs in engorgement on grain) all impair microbial digestion. The microflora also may be adversely affected by the oral administration of drugs that are antimicrobial or that drastically alter the pH of rumen contents.
Gastroenteritis is a broad term that is used in both human and veterinary medicine to describe diseases of the GI tract that commonly result in vomiting and diarrhea, with severe impact upon digestion and absorption of nutrients. When used with precision, the term ‘gastritis’ refers to inflammation of the stomach, ‘enteritis’ refers to inflammation of the small intestine, and ‘colitis’ refers to inflammation of the large intestine. In actual practice, the afore-mentioned terms are often combined to reflect the broad impact of disease across the GI tract, resulting in terms such as gastroenteritis or enterocolitis. This document will subsequently use the term ‘gastroenteritis’ in its broadest sense as a collective noun referring to diseases and abnormalities of the gastrointestinal tract.
Causes of gastroenteritis are commonly divided into infectious and non-infectious causes. These are summarized in the table below.
Common Causes of GastroenteritisCattle,Sheep,andGoatsPigsHorsesDogs and Cats HumansVirusesBovine viralTransmissibleRotavirus,Canine parvovirus, Norovirus,diarrhea,gastroenteritis,vesicularcanine coronavirus,rotavirusrotavirus,porcinestomatitis,felinecoronavirus,circovirus typecoronaviruspanleukopeniarinderpest,II, porcinevirus, feline entericmalignantepidemiccoronavirus, caninecatarrhaldiarrhea virus,and felinefever,rotavirus, foot-rotaviruses, caninebluetongue,and-mouthand felinefoot-and-disease, vesicularastrovirusesmouthstomatitis,diseasevesicularexanthemaRickettsiaeNeorickettsiaNeorickettsiaR. rickettsii.risticiihelminthoeca(Potomac(salmon poisoninghorse feverin dogs)[equinemonocyticehrlichiosis])BacteriaEnterotoxigenicEnterotoxigenicEnterotoxigenic Salmonella spp, Salmonella, EscherichiaE coli,E coli, YersiniaCampylobactercoli,Salmonella spp,Salmonella enterocolitica, Staphylococci, SalmonellaBrachyspiraspp,CampylobacterBacillus cereus,spp,hyodysenteriae,Rhodococcusjejuni, BacillusClostridiumMycobacterium Clostridiumequi, piliformis,perfringens, or paratuberculosis,peifringens typesActinobacillusClostridium spp,Shigella spp; FusobacteriumB and C,equuli,Mycobacterium spp, Escherichia coli;necrophorum,LawsoniaClostridiumShigella spp,ClostridiumClostridiumintracellularis,perfringens types adherent invasive difficileperfringensClostridiumB and C, E coli,(types B, C,difficileClostridiumBrachyspira sppand D),difficile,ActinobacillusLawsonialignieresii,intracellularisYersiniaenterocolitica,Campylobacter jejuniProtozoaEimeria spp,Eimeria spp,Eimeria spp,Isospora spp,Giardia sp,Cryptosporidium Isospora suisCryptosporidium Sarcocystis spp,EntamoebasppsppBesnoitia spp,histolytica,Hammondia spp,Cryptosporidia sppToxoplasma spp,Giardia spp,Tritrichomonasspp, Entamoebahistolytica,Balantidium coli,Cryptosporidium spp,Neospora sppYeast andCandida sppCandida sppAspergillus Histoplasma Candida sppFungi(cattle)fumigatuscapsulatum,Aspergillus spp,Candida albicans,phycomycetesAlgaeProtothecaPrototheca sppPrototheca sppPrototheca sppsppParasitesHaemonchus,Ascaris sp,GasterophilusSpirocerca lupi, monogeneans,(helminths)Ostertagia,Macracanthorhynchusspp,Physaloptera sppcestodesTrichostrongylus sp,HabronemaOllulanus sp(tapeworms),Spp, Oesophagostomumspp, OxyurisStrongyloides spnematodesCooperiaspp,sp,Roundworms (roundworms),Spp,Strongyloides sp,ParascarisHookwormsand trematodesBunostomumTrichuris sp,sp, LargeWhipworms(flukes)Sp,Strongyles,AcanthocephalansStrongyloidesSmallTapewormsSp,Strongyles,FlukesNematodirusStrongyloides Spp,sp,ToxocaraTapeworms,Sp,Trichostrongylus Oesophagostomum sp.Sp,ChabertiaSp,TrichurisSpp,TapewormsInfectious Causes of Gastroenteritis
The GI tract is subject to infection by many pathogens, which are a major cause of economic loss due to illness, suboptimal performance, and death. As explained in the Merck Veterinary Manual, which is incorporated herein as a reference (http://www.merckmanuals.com/vet/digestive_system/digestive_system_introduction/overview_of_digestive_system.html, gastroenteritis may be caused by many different types of bacteria, viruses, and parasites.
Bacterial
Salmonellosis, enterotoxemia, and colibacillosis are examples of bacterial diseases of the GI tract. Many of the bacterial pathogens are part of the normal intestinal flora, and disease develops only after a stressful event, eg, salmonellosis in horses after transportation, or Clostridium difficile diarrhea after surgery in humans.
Clostridia are spore-forming bacteria that occur naturally in the soil and the intestinal tract of animals and humans. Diet change or stress may cause the normally inactive Clostridial bacteria in the intestines to become dominant, thus increasing in numbers and producing toxins. Different Clostridial species produce toxins which have various effects. For example, botulism and tetanus are both caused by Clostridial species. Clostridia perfringens produces an enterotoxin which destroys the tight junctions between the intestinal endothelial cells, resulting in severe diarrhea. Clostridia difficile is a notorious member of the Clostridia family and is the leading cause of hospital-acquired diarrhea in humans (Voth, D. E., & Ballard, J. D. (2005). Clostridium difficile toxins: mechanism of action and role in disease. Clinical Microbiology Reviews, 18(2), 247-63, which is incorporated herein as a reference).
Viral
Viral pathogens that cause disease of the GI tract are highly contagious. Important gastrointestinal viruses in veterinary medicine in include rotavirus, coronavirus, canine parvovirus, feline panleukopenia, bovine viral diarrhea (BVD), swine transmissible gastroenteritis (TGE) and porcine epidemic diarrhea virus (PEDv). Important viral pathogens in humans include noravirus and rotavirus.
Protozoal
Protozoa are one-celled parasites that infect the intestinal cells. Infections of small numbers of protozoa are common, and are often seen during microscopic fecal examinations in patients without evidence of disease. Patients infected with parasites are considered carriers and possible sources of infection for other susceptible animals or humans. The disease is caused by exposure and infections in young animals that have not been previously exposed. In veterinary medicine, common intestinal protozoal diseases include coccidiosis in young ruminants, dogs, cats, and poultry; trichomoniasis and giardiasis in dogs; and hexamitiasis in poultry. These diseases cause enteritis or colitis and are characterized by diarrhea, with or without blood and mucus. In humans, Giardia spp are the most common protozoa. Death from protozoal infection is related to dehydration and anemia. Diagnosis is based on the presence of clinical signs in the patient and detection of protozoa cysts or motile stages in the feces.
Parasitic
GI diseases caused by helminth (worm) parasites are not always clinically apparent, but both clinical and sub-clinical diseases affect the health of the patient. Nematodes (roundworms) are worms that commonly infect the GI tract of animals. Common species include trichostrongyles that infect the stomach and intestines of ruminants; strongyles which infect the large intestine of horses; hookworms which infect the small intestine of dogs and cats; large roundworms infecting the small intestine of pigs, dogs, cats, horses, and poultry; and whipworms infecting the large intestine of dogs and pigs. The parasitic larval stages of botflies (Gasterophilus intestinalis) infest and develop in the stomach of horses. In large numbers, bots may cause stomach pain and signs of colic in horses. Clinically affected horses display obvious signs of disease such as anemia, diarrhea, and emaciation.
The life span of worms is 1 to 12 months depending on the type of worm and level of resistance in the animal. Resistance affects how long the adult worms live and how many larvae survive as they enter an animal.
Large numbers of worms in the GI tract can affect the patient's health by causing a nutritional disturbance. Developing and migrating larvae and feeding adult worms can cause sufficient damage to the stomach lining and intestines. They also interfere with digestion and cause blood loss. Reduced enzyme secretion and nutrient absorption result in digestive inefficiency. Some worms suck blood and cause anemia and hemorrhage. Signs of disease are similar to the signs of malnutrition, including emaciation, changes in skin and hair, diarrhea, and anemia. Migratory larvae of roundworms can cause additional damage to the arteries, liver, and lungs of affected species.
Animals and people become infected when they swallow larvae (hairworms, strongyles, hookworms) or eggs (large roundworms, whipworms), when larvae penetrate the skin (hookworms), or when larvae enter the uterus or colostrum (hookworms, large roundworms).
Prions
Prions have classically been associated with neurological disease, namely transmissible spongiform encephalopathy in sheep, cattle and humans. However, a prion was recently reported to cause chronic diarrhea as well as autonomic nervous system abnormalities and peripheral neuropathy (Mead S, et al “A novel prion disease associated with diarrhea and autonomic neuropathy” N Engl J Med 2013; 369:1904-1914, which is incorporated herein as a reference).
Noninfectious Causes of Gastroenteritis
The major causes of noninfectious disease of the GI tract in all species include dietary overload or indigestible feeds, chemical or physical agents, obstruction of the stomach and intestines caused by the ingestion of foreign bodies or by any physical displacement or injury to the GI tract that interferes with the flow of ingesta, enzyme deficiencies, abnormalities of the mucosa that interfere with normal function (eg, gastric ulcers, inflammatory bowel disease, villous atrophy, neoplasms), and congenital defects. GI manifestations such as vomiting and diarrhea may also develop secondary to systemic or metabolic diseases such as uremia, liver disease, and hypoadrenocorticism.
Osmotic diarrhea is seen when inadequate absorption results in a collection of solutes in the gut lumen, which cause water to be retained by their osmotic activity. It develops in any condition that results in nutrient malabsorption or maldigestion or when an animal ingests a large amount of osmotically active substances that are not absorbed, eg, an overeating puppy or an excessively fatty meal in humans.
Malabsorption is failure of digestion and absorption due to some defect in the villous digestive and absorptive cells, which are mature cells that cover the villi. Intestinal malabsorption also may be caused by any defect that impairs absorptive capacity, such as diffuse inflammatory disorders (eg, lymphocytic-plasmacytic enteritis, eosinophilic enteritis) or neoplasia (eg, lymphosarcoma). Other examples of malabsorption include defects of pancreatic secretion that result in maldigestion. Rarely, because of failure to digest lactose (which, in large amounts, has a hyperosmotic effect), neonatal farm animals or pups may have diarrhea while they are being fed milk.
In noninfectious diseases of the GI tract, usually only a single animal is affected at one time. Exceptions are diseases associated with excessive feed intake or poisons, in which herd outbreaks are common.
Important Diseases Specifically Causing Diarrhea
Pigs: Diarrhea is the most common and probably the most important gastrointestinal disease of pigs, especially young piglets, as mentioned in “The Pig Site”, which is incorporated herein as a reference (http://www.thepigsite.com/pighealth/article/276/diarrhoea-or-scour). In some outbreaks, diarrhea is responsible for high morbidity and mortality. In a well-run herd there should be less than 3% of litters at any one time requiring treatment and piglet mortality from diarrhea should be less than 0.5%. In severe outbreaks, levels of mortality can rise to 7% or more and in individual untreated litters up to 100% (in TGE it may reach 100% overall). Common causes of diarrhea in piglets are shown in the following table:
THE MAIN CAUSES OF PIGLET DIARRHOEAEarly period daysLate period days0-33-77-1415-21Mortality levelAgalactia✓✓✓✓ModerateClostridia✓✓✓HighCoccidiosis✓✓✓LowColibacillosis ✓✓✓Moderate(E. coli)PED✓✓✓✓LowPRRS✓✓✓✓VariableRotavirus✓✓LowTGE✓✓✓✓High
Four of the agents listed in the table are viruses, namely transmittable gastroenteritis (TGE), rotavirus, porcine epidemic diarrhea (PED) and porcine reproductive and respiratory syndrome (PRRS). The main bacterial causes are Escherichia. coli and Clostridia spp. The main parasite is coccidia.
Calves: Calf scours is the term used to describe gastroenteritis in calves. It is commonly incited by rotavirus or coronvirus infections, but other organisms such as Cryptosporidium (a protozoa) may also be causative. Regardless of the cause, calf scours is also complicated by bacterial overgrowth of Escherichia coli in approximately 30% of cases (Constable, P. D. (2004). Antimicrobial use in the treatment of calf diarrhea. Journal of Veterinary Internal Medicine, 18(1), 8-17, which is incorporated herein as a reference) Treatment consists of oral electrolyte solutions and, when appropriate, antimicrobials.
Puppies: Canine parvovirus is the most important cause of infectious diarrhea in young dogs. Parvovirus causes destruction of the intestinal cells, resulting in severe fluid loss and hemorrhagic diarrhea. If untreated, the mortality rate exceeds 80%.
Children: Cholera is an important cause of acute diarrhea in humans, and is caused by the bacteria Vibrio cholerae. Cholera is estimated to affect between 3 and 5 million people per year, and cause over 100,000 deaths. The Vibrio cholerae bacteria produces a toxin which causes the intestinal mucosal cells to secrete large quantities of chloride into the intestinal lumen, with subsequent loss of sodium, water and other electrolytes (http://www.textbookofbacteriology.net/cholera_3.html, which is incorporated herein as a reference) The treatment of choice is oral rehydration solution (http://www.cdc.gov/cholera/general/, which is incorporated herein as a reference).
Pathophysiology Mechanisms of Gastroenteritis
Both infectious and non-infectious causes of gastroenteritis result in a spectrum of disturbances in motility, intestinal distension, vomiting, diarrhea, fluid loss, hypersecretion and malabsorption.
Motility and Distension
Motility of the intestines depends on stimulation via the sympathetic and parasympathetic nervous systems (and thus on the activity of the central and peripheral parts of these systems) and on the GI musculature and its intrinsic nerve plexuses. Abnormal motor function usually manifests as decreased motility. Segmental resistance is usually reduced, and transit rate increases. One of the major consequences of subnormal motility is distention with fluid and gas. Much of the accumulated fluid is saliva and gastric and intestinal juices secreted during normal digestion. Distention causes pain and reflex spasm of adjoining gut segments. It also stimulates further secretion of fluid into the lumen of the gut, which exacerbates the condition. When the distention exceeds a critical point, the ability of the musculature of the intestinal wall to respond diminishes, the initial pain disappears, and paralytic ileus develops in which all GI muscle tone is lost. Dehydration, acid-base and electrolyte imbalance, and circulatory failure are major consequences of GI distention.
Vomiting is a neural reflex act that results in ejection of food and fluid from the stomach through the oral cavity. It is associated with antecedent events such as premonition, nausea, salivation, or shivering and is accompanied by repeated contractions of the abdominal muscles.
Diarrhea is caused by disruption of the normally continuous transfer of electrolytes and water across the intestinal mucosa. Normally, secretion (from bloodstream to intestinal lumen) and absorption (from intestinal lumen to bloodstream) occur simultaneously. In normal health, 99% of the fluid resulting from oral intake and GI tract secretions is reabsorbed by the small intestine and colon. In humans, this is a total fluid load of about 9 of 10 L daily. Thus, even a 1% change in this balance between resorption and secretion can result in significant fluid losses and diarrhea.
Three major pathophysiologic mechanisms result in diarrhea. These are increased permeability, hypersecretion, and villous destruction. Increased permeability caused by inflammation in the intestines can be accompanied by an increase in “pore size” in the intestinal mucosa, permitting increased flow through the membrane (“leak”) down the pressure gradient from blood to the intestinal lumen. If the amount exuded exceeds the absorptive capacity of the intestines, diarrhea results. The size of the material that leaks through the mucosa varies, depending on the magnitude of the increase in pore size. Large increases in pore size permit exudation of plasma protein, resulting in protein-losing enteropathies (eg, lymphangiectasia in dogs, paratuberculosis in cattle, nematode infections). Greater increases in pore size result in the loss of red blood cells, producing hemorrhagic diarrhea (e.g., hemorrhagic gastroenteritis, parvovirus infection, severe hookworm infection).
Hypersecretion is a net intestinal loss of fluid and electrolytes. Hypersecretion can be due to enterotoxins, osmotic load, malabsorption or destruction of the intestinal villi. Enterotoxic colibacillosis is an example of diarrheal disease due to enterotoxins. Certain variants of the bacterial Escherichia coli produce enterotoxin that stimulates the crypt epithelium to secrete fluid beyond the absorptive capacity of the intestines. The fluid secreted is isotonic, alkaline, and free of exudates. The villi, along with their digestive and absorptive capabilities, remain intact. The fact that the villi remains intact is the basis of oral rehydration therapy in this particular disease, because a fluid administered orally that contains glucose, amino acids, and sodium is absorbed, even in the face of hypersecretion.
Transmissible viral diseases often cause destruction of the villi. Some epitheliotropic viruses directly infect and destroy the villous absorptive epithelial cells, e.g., coronavirus, transmissible gastroenteritis virus of piglets, and rotavirus of calves. Feline panleukopenia virus and canine parvovirus destroy the crypt cells, which results in failure of renewal of villous absorptive cells and collapse of the villi; thus regeneration is a longer process after parvoviral infection than after viral infections of villous tip epithelium (eg, coronavirus, rotavirus). Reduced secretion of digestive enzymes at the surface of villous tip cells is characteristic of epitheliotropic viral infections recognized in farm animals.
Clinical Findings of GI Disease
Signs of GI disease include excessive salivation, diarrhea, constipation or scant feces, vomiting, regurgitation, GI tract hemorrhage, abdominal pain and distention, tenesmus, shock and dehydration, weight loss and suboptimal performance. Vomiting is most common in single-stomached animals and humans. Horses, rabbits and ruminants do not vomit. Large-volume, fluid diarrhea usually is associated with hypersecretion (eg, in enterotoxigenic colibacillosis in newborn calves) or with malabsorptive (osmotic) effects. Blood and fibrinous casts in the feces indicate a hemorrhagic, fibrinonecrotic enteritis of the small or large intestine, eg, bovine viral diarrhea, coccidiosis, salmonellosis, or swine dysentery. Abdominal distention can result from accumulation of gas, fluid, or ingesta. Varying degrees of dehydration and acid-base and electrolyte imbalance, which may lead to shock and death, are seen when large quantities of fluid are lost through vomiting or diarrhea.
Treatment and Control of Gastroenteritis
Whenever possible, elimination of the cause of the disease or the source of the infection is the primary objective. Elimination of the primary cause may involve antimicrobials, coccidiostats, antifungal agents, anthelmintics, antidotes for poisons, or surgical correction of displacements. In epidemic situations such as swine dysentery and human cholera, massive disinfection and development of clean water sources may be required.
After the cause or source is eliminated, treatment is supportive and symptomatic, aimed at relieving pain, correcting fluid and electrolyte abnormalities, and providing such nutritional support as can be tolerated by the patient.
Replacement of fluid and electrolytes is necessary when dehydration and electrolyte and acid-base imbalance occur as in diarrhea, persistent vomiting, intestinal obstruction, or torsion of the stomach(s), in which large amounts of fluid and electrolytes are sequestered. An oral glucose-electrolyte solution can be given if diarrhea is not severe and nausea and vomiting are minimal. Severe diarrhea requires fluid and electrolyte replacement to correct dehydration, electrolyte imbalance, and acidosis. Oral and parenteral (intravenous) fluids are sometimes given simultaneously when water and electrolytes must be replaced in massive amounts. Intravenous fluids containing sodium chloride, potassium, glucose and bicarbonate precursor molecules such as lactate and acetate are often administered to individual patients, but their use is precluded in farm animal herd situations and in some human epidemic situations.
Correction of excessive or depressed motility appears rational, but often the nature and degree of abnormal motility are uncertain; in addition, available drugs may not give consistent results. There is little clinical evidence to recommend the routine use of anticholinergic or opioid drugs to slow intestinal transit. Slowing intestinal transit may be counterproductive to the defense mechanism of diarrhea, which acts to evacuate harmful organisms and their toxins. In general, anticholinergic drugs probably are justified only for short-term symptomatic relief of pain and tenesmus associated with inflammatory diseases of the colon and rectum. In some disorders of gastric or colonic motility, prokinetic drugs (eg, metoclopramide, erythromycin) may be useful.
Relief of distention medically by stomach tube (as in bloat in ruminants) or surgically (as in acute intestinal obstruction, or in torsion of the abomasum in ruminants or of the stomach in monogastric animals) may be required. The GI tract may become distended with gas, fluid, or ingesta at any level due to physical or functional obstruction.
Relief of abdominal pain by administration of analgesics should be done when the pain is reflexly affecting other body systems (eg, cardiovascular collapse) or when it is causing the animal to injure itself because of rolling, kicking, or throwing itself. Animals treated with analgesics must be monitored regularly to ensure that the relief of pain does not provide a false sense of security; the lesion may be progressively worsening while the animal is under the influence of the analgesic. Reconstitution of ruminal flora should be done in situations in which the ruminal flora may be seriously depleted (eg, in prolonged anorexia or acute indigestion). Transfaunation (ruminal fluid transfer) involves oral administration of ruminal contents from a healthy animal that contains rumen bacteria and protozoa and volatile fatty acids.